Intracellular interactions under oxidative stress and aging: a hypothesis.

Oxygen-derived free radicals may result from various reactions, both intra- and extracellularly, but generation of oxygen free radicals from electrons escaping from the electron transport chain in mitochondria is by far the predominant process during the lifetime of a "normal", healthy cell. There is clear evidence that mitochondria are also an important target for oxygen-derived free radicals, and the resulting mitochondrial malfunction has long been suggested as the intracellular basis of aging. Moreover, there is clear evidence that free radical-dependent reactions lead to lipofuscin formation and its accumulation in Lysosomes of post-mitotic cells. Lipofuscin accumulation was demonstrated to be dependent on the probability of iron-catalyzed Fenton reactions. A hypothesis is presented which assumes free radical dependent reactions in mitochondria and lysosomes to be interdependent. Production of hydrogen peroxide in mitochondria and its subsequent diffusion in the cytoplasm, and Fenton reactions in lysosomes, transferring hydrogen peroxide intra-lysosomally to the highly cytotoxic hydroxyl radical, are thought to be necessary intermediary steps in the generation of mitochondrial damage. On the other hand, damage to mitochondria increases both mitochondrial output of hydrogen peroxide and lipofuscin accumulation.